On Dec. 31, 2019, Chinese health officials informed the World Health Organization (WHO) about cases of pneumonia in Wuhan, a city in Hubei province, with an unknown cause. By Jan. 7, 2020, Chinese authorities had determined that these pneumonia cases were traceable to a newly identified virus that was part of the coronavirus family. They labelled the infection “coronavirus disease 2019”—COVID-19 for short.
At first, the virus itself was called “2019-novel coronavirus” (2019-nCoV); an international group of scientists later renamed it “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2). By Jan. 12, Chinese scientists determined the genetic sequence of SARS-CoV-2 and shared this information with the global scientific community, which made it possible to start developing diagnostic tests and identifying potential treatments and vaccines.
Within months, thousands of drugs had been screened for activity against COVID-19, including many drugs that were already approved for treating other conditions, and other drugs that were still experimental. By the end of May, some 100 clinical trials including antiviral drugs to treat COVID-19 were completed or underway throughout the world. Study results for the most anticipated new treatment, remdesivir, were published in the New England Journal of Medicine on May 22, showing that remdesivir shortened the time to recovery in adults hospitalized with COVID-19 compared to placebo.
This series of developments was more than just remarkable—it was astounding! Within a five-month period, the international medical community had gone from observing a completely new disease, to identifying the virus that caused it, to conducting clinical trials of a promising new treatment that showed positive, if not definitive, results.
While COVID-19 is among the most deadly and devastating viral pandemics the world has ever seen, it may also prove to be a shining moment for medical science. Imagine if, at his famous address to Congress in 1961, President John F. Kennedy had declared the goal of sending a person to the moon by the end of the decade, and then Neil Armstrong had taken his historic moonwalk five months later! That is what the scientific response to COVID-19 has been like, compared to the previous 50 years of antiviral research and treatment. Let’s take a closer look.
People get infectious diseases from different types of microscopic organisms: viruses, bacteria, fungi, and parasites (protozoa and worms). Together, all these organisms are called microbes, and the drugs that treat them are called antimicrobial agents.
The world’s first antimicrobial drugs were antibiotics—drugs used to treat bacterial infections. Three great landmarks in the early history of antimicrobial drugs were the development of salvarsan, a treatment for syphilis, in 1910; the development of sulfonamides (commonly called sulfa drugs) in the 1930s; and the development of penicillin in the 1940s. The first antiviral drug was Dendrid (idoxuridine), an ophthalmic solution (eye drops) approved by the U.S. Food and Drug Administration (FDA) in 1963 to treat eye infections caused by the herpes simplex virus.
It was the genital herpes epidemic of the 1970s that really got the antiviral era going. In November 1981, a headline in the FDA Consumer shouted, “Herpes Thrives on the Sexual Revolution.” The teaser read, “A highly contagious, sexually transmitted disease whose symptoms sometimes come and go without warning—that’s genital herpes. Cases have increased in recent years, and so far there is no effective treatment.” Several months later, Time magazine declared genital herpes “the new scarlet letter” and warned that “herpes, an incurable virus, threatens to undo the sexual revolution.” In 1982, the FDA approved Zovirax (acyclovir) ointment to treat genital herpes—and with that, the antiviral era entered high gear.
But as the media made light of the sexual revolution and the genital herpes epidemic, something darker was coming over the horizon.
In 1981, the first cases of a rare skin cancer called Kaposi’s sarcoma appeared in gay men, as well as cases of an uncommon fungal disease called Pneumocystis carinii pneumonia (PCP, later renamed Pneumocystis jirovecii). This was the beginning of what would come to be called Acquired Immune Deficiency Syndrome—the AIDS epidemic had begun.
When AIDS first appeared, nobody even knew that it was caused by a virus. Once AIDS was determined to be a viral disease, it took some time to identify the virus that caused AIDS—the human immunodeficiency virus, or HIV (identified in 1983). Once HIV was identified, it took some time to develop tests for it (the first tests became available in 1984). Once there were tests for it, it took some time to develop drugs that were effective against it.
The first drug to treat HIV was azidothymidine (AZT), approved in 1987 and marketed under the brand name Retrovir. AZT helped, but not enough, and not for long. After being on AZT for a period of time, people with AIDS invariably experienced viral resistance to the drug—meaning AZT stopped working.
The mechanism of resistance was genetic mutation. Viruses, like other organisms, are constantly evolving. But where plants or animals might take thousands of years to express a new genetic trait, a virus can switch up its genetic makeup much more quickly to fake out an antiviral drug. In the presence of AZT (with no other drugs on board to help AZT inhibit the virus), the HIV in an individual patient can change its genetic structure—develop antiviral resistance—within a year.
How and why does that happen? Antiviral drugs work by interfering with viral enzymes—proteins that regulate the life cycle of the virus and allow it to reproduce (replicate). AZT inhibits an enzyme called reverse transcriptase (it belongs to a class of drugs called reverse transcriptase inhibitors), which HIV uses to convert its ribonucleic acid (RNA) into deoxyribonucleic acid (DNA), a process called reverse transcription—sort of like using a photographic negative to develop a print, or using an audio master recording to press vinyl record albums (viruses are very analog).
As Darwinian evolutionary theory teaches us, evolution is based on the survival of the fittest. Any population in nature, be it animals, plants, or microbes, has a certain amount of genetic variation—affecting things like height, weight, hair color, eye color, resistance to disease, etc. When a virus is exposed to an antiviral drug, some copies of the virus will be a bit more resistant to the drug than others. The more susceptible viruses will get zapped by the drug; the more resistant viruses will live to pass their genetic traits on to the next viral generation.
Over time, the drug-susceptible population (called wild-type virus) more or less disappears from the viral population in the infected person’s body, while the resistant (mutant) virus takes over. Soon, viral levels are as high as they were before the drug came on the scene, only now the viral population is resistant to the drug, and the disease returns in full force. In the case of HIV and AZT, people with AIDS who had been on the mend after they first started taking AZT began to get sicker again after months on the drug.
The discovery of AZT resistance was a game-changer for AIDS research and treatment—a bad outcome that pointed the way towards better treatment strategies. Before, the name of the antiviral game was potency—how effective the drug was at stopping viral replication. Now, the game also required durability—beating viral resistance. Sure, drugs had to work, but they also had to keep working over a sustained period of time.
In the wake of AZT, a number of other reverse transcriptase inhibitors were approved: Videx (didanosine or ddI), Hivid (zalcitabine or ddC), Zerit (stavudine or d4T), and Epivir (lamivudine or 3TC). The virus developed resistance to all of them. People with AIDS on these treatments, hoping for a medical miracle, got better with each new drug, then got sicker again once the virus developed resistance.
For a while, researchers kept looking for the one drug that would prove sufficiently potent and durable against the virus—one drug that would keep the virus at bay, and to which the virus would not develop resistance. But that was not in the cards. What’s more, potency and durability were like two sides of a single coin: Antiviral drug resistance emerges in the presence of viral replication; if the drug is not potent enough to suppress the virus completely, then even a small amount of ongoing replication will eventually lead to resistance.
By the early 1990s, first in clinical practice, then in clinical studies, providers treating people with HIV and AIDS were using two-drug combinations in an attempt to increase efficacy (effectiveness) and reduce or eliminate resistance—including the combinations AZT/ddI, AZT/ddC, and ddI/ddC. Despite some hopeful signs, none of these combinations did the trick—not in terms of efficacy, durability, or even tolerability (side effects).
In 1995, studies showed that the combination of Retrovir and Epivir was better than treatment with either drug alone, and also better than other combinations.
In 1996, a whole new class of HIV drugs became available. These drugs inhibited another viral enzyme, called protease. These protease inhibitors were combined with reverse transcriptase inhibitors in three-drug combinations (the “cocktail”) that, for the first time, provided effective, durable, lifesaving treatment for HIV infection and AIDS.
There is more to the story of antiviral drugs—much more than we have room for here. But the most striking takeaway is that, in the 30 years after the approval of Retrovir in 1987, more than 80 other antiviral drugs were approved by the FDA for use in the U.S. These drugs fall into 13 different drug classes and treat nine different infectious diseases—including HIV, hepatitis B, hepatitis C, herpes simplex virus, influenza, cytomegalovirus, varicella-zoster virus (the virus that causes both chicken pox and shingles), respiratory syncytial virus, and human papillomavirus (the virus that causes anal and genital warts).
Now, of course, humankind is facing a new viral pandemic in COVID-19. Because of scientific developments that started at the beginning of the last century, were spurred on by the herpes epidemic in the 1970s, and reached a frantic pitch with the AIDS epidemic in the 1980s, work on antiviral drugs to treat COVID-19 has already proceeded at lightning speed.
A scant six months into the epidemic, the FDA has not yet approved any treatments for COVID-19—but clinical trials are rapidly pointing the way towards both experimental drugs, like remdesivir, and drugs already approved to treat other diseases, including drugs approved to treat HIV.
The journey from Dendrid, the first FDA-approved antiviral, to remdesivir, which may well be the next antiviral approved, has been long and has included a lot of heartbreak—especially the 15-year wait for effective treatments for HIV and AIDS. But the view back is full of heroic accomplishments, and the road ahead holds much promise, and even more hope.